The halichondrins are polyether macrolides, originally isolated from the marine sponge Halichondria okadai by Uemura, Hirata, and coworkers. Due to their intriguing structural architecture and extraordinary in vitro and in vivo anti-proliferative activity, the halichondrins have received much attention from the scientific community. Synthetic methods that streamline the preparation of these natural products or related derivatives are important given the structural complexity of the halichondrin backbone. A highly convergent approach has been adopted to synthesize halichondrins and analogs thereof. Because of its high degree of convergence, one can expect a high overall efficiency for the longest linear synthetic sequence. Interestingly, the key two couplings have been achieved efficiently with Ni/Cr-mediated reactions: one between the building blocks C20-C38 and C1-C19 to synthesize the macrolide; and another between a vinyl iodide and an aldehyde to synthesize the building block C1-C19. The structure of Halichondrin B is shown below, with carbon atoms numbered.

Chromium-mediated couplings of organic halides/triflates with aldehydes belong to a class of 1,2-carbonyl addition reactions. In this process, the active nucleophiles RCrX3 are generated from halides/triflates in situ. Depending on the mode of activation, chromium-mediated couplings are divided into three sub-groups: (1) Ni/Cr-mediated alkenylation, alkynylation, and arylation, (2) Co or Fe/Cr-mediated alkylation, 2-haloallyl-ation and propargylation, and (3) Cr-mediated allylation and propargylation (See, e.g., Saccomano, N. A. in Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1, p 173).
Ni/Cr-mediated couplings of alkenyl halides/triflates with aldehydes were originally reported by Takai, Hiyama, Nozaki, and coworkers in 1983. Since then, it has been shown that the coupling is initiated by a catalytic amount of NiCl2 as a contaminant in the with CrCl2. It is now generally accepted that this coupling involves: (1) oxidative addition of Ni(0), formed from NiCl2 via reduction with CrCl2 in situ, to an alkenyl halide/triflate to form an alkenyl Ni(II)-species, (2) transmetallation of the resultant Ni(II)-species to Cr(II)Cl2 to form alkenyl Cr(III)-species, and (3) carbonyl addition of the resultant Cr(III)-species to an aldehyde to form the product Cr(III)-alkoxide (FIG. 5). Chemistry has been developed to achieve this coupling in a catalytic and asymmetric manner.
Due to the important biological activities of halichondrins, it is valuable to develop a unified and practical synthesis of the C1-C19 building block, as well as C20-C38 building blocks, to allow easy access to halichondrins (e.g., halichondrin A, B, C; norhalichondrin A, B, C; homohalichondrin A, B, C; eribulin), and analogs thereof.